Pulmonary fibrosis is a scarring or thickening of the lungs that causes shortness of breath, a dry cough, fatigue, chest discomfort, weight loss, a decrease in the ability of the lungs to transmit oxygen to the blood stream, and, eventually, heart failure. Cells known as myofibroblasts normally secrete materials that are required for wound healing; once the wound has closed, the cells disappear. In pulmonary fibrosis, the myofibroblasts stick around, continuing to secrete wound healing factors that cause fibrosis in the lungs. Yong Zhou and colleagues at the University of Alabama at Birmingham identified a mechanosensitive cellular signaling pathway in myofibroblasts that is activated by the hardening of fibrotic tissue. Activation of this pathway promotes myofibroblast survival and prevents the normal disappearance of these cells after completion of wound healing. The pathway is dependent on a protein known as ROCK. Zhou and colleagues found that a drug that inhibits ROCK, fasudil, attenuates the pro-survival pathway and causes myofibroblasts to die. Further, fasudil treatment protected mice from injury-induced lung fibrosis. In the accompanying images, myofibroblasts were grown on a soft matrix (left), a stiff matrix (middle), or were grown on a stiff matrix and treated with fasudil, then stained for F-actin (red) and smooth muscle actin (green), which indicate activation of fibrotic pathways. These studies suggest that ROCK inhibitors could be used to treat pulmonary fibrosis.
Matrix stiffening and myofibroblast resistance to apoptosis are cardinal features of chronic fibrotic diseases involving diverse organ systems. The interactions between altered tissue biomechanics and cellular signaling that sustain progressive fibrosis are not well defined. In this study, we used ex vivo and in vivo approaches to define a mechanotransduction pathway involving Rho/Rho kinase (Rho/ROCK), actin cytoskeletal remodeling, and a mechanosensitive transcription factor, megakaryoblastic leukemia 1 (MKL1), that coordinately regulate myofibroblast differentiation and survival. Both in an experimental mouse model of lung fibrosis and in human subjects with idiopathic pulmonary fibrosis (IPF), we observed activation of the Rho/ROCK pathway, enhanced actin cytoskeletal polymerization, and MKL1 cytoplasmic-nuclear shuttling. Pharmacologic disruption of this mechanotransduction pathway with the ROCK inhibitor fasudil induced myofibroblast apoptosis through a mechanism involving downregulation of BCL-2 and activation of the intrinsic mitochondrial apoptotic pathway. Treatment with fasudil during the postinflammatory fibrotic phase of lung injury or genetic ablation of
Yong Zhou, Xiangwei Huang, Louise Hecker, Deepali Kurundkar, Ashish Kurundkar, Hui Liu, Tong-Huan Jin, Leena Desai, Karen Bernard, Victor J. Thannickal